A new insight into the treatment of factor V deficiency.

2021 ◽  
Author(s):  
SULEIMAN DAMIEN
Keyword(s):  
Messenger Rna ◽  
Genetic Disorders ◽  
Lipid Nanoparticles ◽  
Therapeutic Effects ◽  
Factor V ◽  
Medical Field ◽  
Factor V Deficiency ◽  
Fatal Bleeding ◽  
Bleeding Episodes ◽  
Insight Into

Inherited factor V deficiency is an extremely rare bleeding disorder with no proper treatment currently available and can result in fatal bleeding episodes for the most severe cases. It is characterized by mutations on the F5 gene and provokes reduced levels and activity of factor V (FV) , a critical protein involved in the coagulation process. One of the most promising biotechnologies in the medical field to tackle similar genetic disorders is the use of messenger RNA, being studied for the management of several conditions. Messenger RNA can be encapsulated into lipid nanoparticles, another promising non-viral delivery system. This present article will detail the possible therapeutic effects of a composition of FV mRNA encapsulated in LNPs, by hypothesizing its details, evaluating the possible treatment and suggesting a possible experimental study that may provide further data about this treatment.

scholarly journals Refractory Epistaxis due to Severe Factor V Deficiency with Inhibitor

2015 ◽  
Vol 2015 ◽  
pp. 1-3
Author(s):  
Elizabeth S. John ◽  
Minesh D. Patel ◽  
Julio Hajdenberg
Keyword(s):  
Case Reports ◽  
Factor V ◽  
Beta Lactamase ◽  
Consensus Guidelines ◽  
Therapeutic Approaches ◽  
Bovine Thrombin ◽  
Complicated Case ◽  
Factor V Deficiency ◽  
Inhibitor Titer ◽  
Insight Into

Factor V deficiency secondary to inhibitors is extremely rare and can be caused by a wide collection of exposures such as bovine thrombin and beta lactamase antibiotics. The management of factor V deficiency with inhibitor is a condition treated based on case reports due to the rarity of this condition. We describe a complicated case of an elderly patient with severe factor V deficiency with high inhibitor titer refractory to FEIBA (anti-inhibitor coagulation complex) treated with NovoSeven concurrently with cyclosporine immunosuppression and Rituxan. Given that there are no consensus guidelines on treatment, this case offers important insight into the therapeutic approaches that can be used to treat such patients.

Novel Factor V C2-Domain Mutation (R2074H) in Two Families with Factor V Deficiency and Bleeding

2002 ◽  
Vol 87 (02) ◽  
pp. 294-299 ◽  
Author(s):  
I. Schrijver ◽  
R. Houissa-Kastally ◽  
C. D. Jones ◽  
K. C. Garcia ◽  
J. L. Zehnder
Keyword(s):  
Hemophilia A ◽  
Point Mutations ◽  
Amino Acid Position ◽  
Protein Domain ◽  
Sequence Variant ◽  
Factor V ◽  
C2 Domain ◽  
Domain Modeling ◽  
Factor V Deficiency ◽  
Bleeding Episodes

SummaryThe molecular basis of Factor V deficiency has been defined in few patients only. We report a homozygous nucleotide change (G6395A) in two Tunisian probands with Factor V deficiency and bleeding episodes. This substitution results in the replacement of an arginine (R) by a histidine (H) in amino acid position 2074, located in the Factor V C2-domain. Mutations in this protein domain have not previously been described. Several lines of evidence support that this sequence variant is indeed disease causing: 1) Crystal structures of Factor V and molecular C2-domain modeling studies of H2074 suggest that the conserved R2074 is required for correct folding; 2) Structure-function studies of selective Factor V mutants (R2074A) demonstrate the importance of R2074 for structural stability of the Factor V C2-domain and for cofactor activity (1); 3) In Factor VIII, point mutations in codon 2209, which corresponds to position 2074 in Factor V, cause hemophilia A.

Congenital Factor V Deficiency: Comparison of the Severity of Clinical Presentations among Patients with Rare Bleeding Disorders

2014 ◽  
Vol 133 (2) ◽  
pp. 148-154 ◽  
Author(s):  
Majid Naderi ◽  
Shadi Tabibian ◽  
Shaban Alizadeh ◽  
Soudabeh Hosseini ◽  
Farhad Zaker ◽  
...  
Keyword(s):  
Clinical Manifestations ◽  
Clinical Findings ◽  
High Rate ◽  
Factor V ◽  
Bleeding Diathesis ◽  
Factor V Deficiency ◽  
Life Threatening ◽  
Grade Ii ◽  
Bleeding Episodes ◽  
Fxiii Deficiency

Background: Factor V deficiency (FVD) is a rare bleeding disorder (RBD) mostly present in regions with a high rate of consanguinity. FVD after FXIII deficiency is the next more prevalent RBD in Sistan and Baluchistan (S&B) in southeastern Iran. The aim of this study was to evaluate the clinical manifestations and severity of bleeding diathesis in patients with FVD. Methods: This descriptive study was conducted on 23 patients with FVD in S&B province. FVD was diagnosed by clinical findings and routine laboratory tests. Bleeding diatheses were classified into three grades (I-III) depending on the severity of symptoms. The severity of bleeding episodes in our patients was compared with other RBDs. Result: Based on residual plasma FV activity, 6 (26%), 16 (69.5%) and 1 (4.5%) patients had mild, moderate and severe factor deficiency, respectively. 24% of the patients had grade III life-threatening bleeding episodes which in comparison with FVII deficiency (17.4%) and FI deficiency (21%) had a higher incidence, and in comparison with FX deficiency (41.7%) and FXIII deficiency (63.1) had a lower incidence. Grade II and grade I bleeding diathesis were observed in 56.2 and 16.7% of the patients, respectively. Conclusion: FVD is the second most common type of RBD in S&B province and grade II bleeding episodes were the major bleeding presentation and observed in more than half of the patients.

Residual platelet factor V ensures thrombin generation in patients with severe congenital factor V deficiency and mild bleeding symptoms

Blood ◽  
2010 ◽  
Vol 115 (4) ◽  
pp. 879-886 ◽  
Author(s):  
Connie Duckers ◽  
Paolo Simioni ◽  
Luca Spiezia ◽  
Claudia Radu ◽  
Paolo Dabrilli ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Thrombin Generation ◽  
Platelet Rich Plasma ◽  
Coagulation Factor ◽  
Factor V ◽  
Platelet Factor ◽  
Factor V Deficiency ◽  
Undetectable Plasma ◽  
Fatal Bleeding ◽  
Tissue Factor Pathway

Abstract Coagulation factor V (FV), present in plasma and platelets, is indispensable to thrombin formation, yet patients with undetectable plasma FV seldom experience major bleeding. We used thrombin generation assays to explore the role of platelet FV in 4 patients with severe congenital FV deficiency (3 with plasma FV clotting activity [FV:C] < 1%). When triggered with tissue factor (TF) concentrations up to 50pM, platelet-poor plasma (PPP) from the patients with undetectable plasma FV showed no thrombin generation, whereas platelet-rich plasma (PRP) formed thrombin already at 1 to 5pM of TF. Thrombin generation in PRP from the FV-deficient patients was enhanced to near-normal levels by platelet activators (collagen or Ca2+-ionophore) and could be completely suppressed by specific FV inhibitors, suggesting FV dependence. Accordingly, platelet FV antigen and activity were measurable in all FV-deficient patients and platelet FVa could be visualized by Western blotting. Normalization of the tissue factor pathway inhibitor (TFPI) level, which is physiologically low in FV-deficient plasma, almost completely abolished thrombin generation in PRP from the FV-deficient patients. In conclusion, patients with undetectable plasma FV may contain functional FV in their platelets. In combination with low TFPI level, residual platelet FV allows sufficient thrombin generation to rescue these patients from fatal bleeding.

Major Surgery in a Subject with Factor V Deficiency

1971 ◽  
Vol 25 (03) ◽  
pp. 438-446 ◽  
Author(s):  
E. J Melliger ◽  
F Duckert
Keyword(s):  
Intercellular Space ◽  
Correct Diagnosis ◽  
Postoperative Bleeding ◽  
Major Surgery ◽  
Factor V ◽  
Factor V Deficiency ◽  
Disappearance Time ◽  
Fresh Plasma ◽  
One Year

SummaryA further case of parahaemophilia is reported. One year after the correct diagnosis had been made the patient had to undergo cholecystectomy which was performed under prophylactic substitutive treatment with fresh plasma at a factor V level of 31 %. A minimal factor V level of 11 to 12% was maintained throughout the first week after operation. There was no abnormal postoperative bleeding. The half disappearance time of factor V was found to be about 12 h. Infusion of equivalent amounts of fresh plasma supplied a higher yield of factor V in the patient’s plasma before operation than postoperatively what may be explained by an increased diffusion of factor V into the intercellular space resulting from a postoperatively increased capillar permeability. The results are compared with those of other authors.

Molecular Characterization of a Type I Quantitative Factor V Deficiency in a Thrombosis Patient that Is “Pseudo Homozygous” for Activated Protein C Resistance

1997 ◽  
Vol 77 (02) ◽  
pp. 252-257 ◽  
Author(s):  
Joan F Guasch ◽  
Ruud P M Lensen ◽  
Rogier M Bertina
Keyword(s):  
Protein C ◽  
Dna Analysis ◽  
Activated Protein C ◽  
Type I ◽  
Factor V ◽  
Sequencing Analysis ◽  
Apc Resistance ◽  
Quantitative Factor ◽  
Factor V Deficiency ◽  
Fv Leiden

SummaryResistance to activated protein C (APC), which is associated with the FV Leiden mutation in the large majority of the cases, is the most common genetic risk factor for thrombosis. Several laboratory tests have been developed to detect the APC-resistance phenotype. The result of the APC-resistance test (APC-sensitivity ratio, APC-SR) usually correlates well with the FV Leiden genotype, but recently some discrepancies have been reported. Some thrombosis patients that are heterozygous for FV Leiden show an APC-SR usually found only in homozygotes for the defect. Some of those patients proved to be compound heterozygotes for the FV Leiden mutation and for a type I quantitative factor V deficiency. We have investigated a thrombosis patient characterized by an APC-SR that would predict homozygosity for FV Leiden. DNA analysis showed that he was heterozygous for the mutation. Sequencing analysis of genomic DNA revealed that the patient also is heterozygous for a G5509→A substitution in exon 16 of the factor V gene. This mutation interferes with the correct splicing of intron 16 and leads to the presence of a null allele, which corresponds to the “non-FV Leiden” allele. The conjunction of these two defects in the patient apparently leads to the same phenotype as observed in homozygotes for the FV Leiden mutation.

Surface Modified Nanoparticulate Carriers for the Targeted Treatment of Breast Cancer

2015 ◽  
Vol 8 (1) ◽  
pp. 2698-2714
Author(s):  
Neeraj Mishra ◽  
Tejinder Singh ◽  
Nidhi ◽  
Supandeep Singh Hallan ◽  
Veerpal Kaur
Keyword(s):  
Breast Cancer ◽  
Tumor Targeting ◽  
Lipid Nanoparticles ◽  
Targeted Treatment ◽  
Therapeutic Effects ◽  
Target Drug Delivery ◽  
Target Drug ◽  
Therapeutic Outcomes ◽  
Lipid Nanocarriers ◽  
Surface Modified

Breast cancer left overs one of the greatest common metastasis disease in females. Advanced diagnostic devices and better understanding of tumour biology can extend the better therapeutic outcomes. Nanotechnology is a tool that helps in cancer diagnosis and treatment therapy. Many nanocarriers such as solid lipid nanoparticles, magnetic nanoparticles, nanocrystals, nanogels, nano-lipid nanocarriers, biodegradable nanoparticles, liposomes, and dendrimers are introduced to improve the therapeutic efficacy of antineoplastic agents. Surface modified target drug delivery system has the potential to increase the therapeutic effects and also reduce the cytotoxicity of breast cancer. Different approaches have been explored for treatment of breast cancer. This review describes the recent advances in the development of nanocarriers used for the targeted treatment of breast cancer. It also focuses on etiology, risk factor and conventional therapy of breast cancer. KEYWORDS: Breast Cancer; Nano-carriers; Tumor Targeting; Ligands; Receptor.

scholarly journals Intracellular Routing and Recognition of Lipid-Based mRNA Nanoparticles

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 945
Author(s):  
Christophe Delehedde ◽  
Luc Even ◽  
Patrick Midoux ◽  
Chantal Pichon ◽  
Federico Perche
Keyword(s):  
Gene Therapy ◽  
Immune Responses ◽  
Transient Expression ◽  
Messenger Rna ◽  
Lipid Nanoparticles ◽  
Delivery Systems ◽  
Clinical Applications ◽  
Cellular Proteins ◽  
Mrna Sequence ◽  
Cytoplasmic Expression

Messenger RNA (mRNA) is being extensively used in gene therapy and vaccination due to its safety over DNA, in the following ways: its lack of integration risk, cytoplasmic expression, and transient expression compatible with fine regulations. However, clinical applications of mRNA are limited by its fast degradation by nucleases, and the activation of detrimental immune responses. Advances in mRNA applications, with the recent approval of COVID-19 vaccines, were fueled by optimization of the mRNA sequence and the development of mRNA delivery systems. Although delivery systems and mRNA sequence optimization have been abundantly reviewed, understanding of the intracellular processing of mRNA is mandatory to improve its applications. We will focus on lipid nanoparticles (LNPs) as they are the most advanced nanocarriers for the delivery of mRNA. Here, we will review how mRNA therapeutic potency can be affected by its interactions with cellular proteins and intracellular distribution.

scholarly journals Ionizable lipid nanoparticles for in utero mRNA delivery

2021 ◽  
Vol 7 (3) ◽  
pp. eaba1028
Author(s):  
Rachel S. Riley ◽  
Meghana V. Kashyap ◽  
Margaret M. Billingsley ◽  
Brandon White ◽  
Mohamad-Gabriel Alameh ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Gene Editing ◽  
Genetic Diseases ◽  
Lipid Nanoparticles ◽  
In Utero ◽  
Luciferase Mrna ◽  
Fetal Size ◽  
Mouse Fetuses ◽  
Clinical Advances ◽  
Immature Immune System

Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)–mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent. We developed a library of ionizable lipid nanoparticles (LNPs) for in utero mRNA delivery to mouse fetuses. We screened LNPs for luciferase mRNA delivery and identified formulations that accumulate within fetal livers, lungs, and intestines with higher efficiency and safety compared to benchmark delivery systems, DLin-MC3-DMA and jetPEI. We demonstrate that LNPs can deliver mRNAs to induce hepatic production of therapeutic secreted proteins. These LNPs may provide a platform for in utero mRNA delivery for protein replacement and gene editing.

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